The emergence of immuno-oncology (IO) has led to revolutionary changes in the field of cancer treatment. Despite notable advancements in this field, a thorough exploration of its full depth and extent has yet to be performed. This study provides a comprehensive overview of publications pertaining to IO. Publications on IO from 2014 to 2023 were retrieved by searching the Web of Science Core Collection database (WoSCC). VOSviewer software and Citespace software were used for the visualized analysis. A total of 1,874 articles have been published in the IO domain. The number of publications and citations has been increasing annually. This study also examines the primary research directions within the field of IO. In conclusion, this study offers a comprehensive overview of the opportunities and challenges associated with IO, illuminating the current status of research and indicating potential future trajectories in this rapidly progressing field. This study provides a comprehensive survey of the current research status and hot spots within the field of IO. It will assist researchers in comprehending the current research emphasis and development trends in this field and offers guidance for future research directions.

Photodynamic (PDT) and chemodynamic therapies (CDT) relying on reactive oxygen species-mediated treatments mainly face various challenges of hypoxia, endogenous hydrogen peroxide (H2O2) deficiency, and glutathione (GSH) overexpression in the tumor microenvironment. Herein, we propose a novel strategy using a core-shell structured nanocomposite, UCNP@mSiO2@5-ALA-CaO2-Cu(UA@CC). The strategy centers on upconverting NPs and then utilizes mesoporous silica loaded with 5-aminolevulinic acid (5-ALA) to maximize the enrichment of protoporphyrin IX (Pph IX), an intra-tumor photosensitizer. Then in the acidic tumor microenvironment (TME), CaO2 in the outer layer reacts with H2O to form O2, H2O2 and Ca2+, and the released H2O2 serves as an auxiliary "fuel" to induce acceleration of the Fenton-like (Cu2+) reaction and inactivation of the antioxidant GSH enzyme, thus enhancing the tumor cells' Catalysis. Furthermore, under the excitation of a 980 nm laser, 5-ALA-mediated PDT and Cu+-based CDT were initiated. Through interconnected processes of Ca2+ overload, self-supply of H2O2/O2, and enhanced GSH depletion, an accelerated cycling strategy for combined PDT/CDT therapy was established, resulting in amplified oxidative stress and anti-tumor capabilities, which was validated in cancer cells and melanoma mouse models.

Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.

The CHEK2 gene serves a canonical role in the DNA damage response (DDR) pathway encoding the regulatory kinase CHK2 in the homologous recombination (HR) repair of double-strand breaks (DSB). Although CHEK2 is traditionally considered a tumor suppressor gene, recent studies suggest additional functions. Across several cohort studies, CHEK2 expression was negatively correlated with the efficacy of immune checkpoint inhibitors (ICI), which target the interaction between effector immune and tumor cells. This review explores two possible explanations for this observed phenomenon: the first relating to the canonical role of CHEK2, and the second introducing a novel role of the CHEK2 gene in immunomodulation of the tumor microenvironment (TME). DDR mutations have been implicated in increased levels of tumor mutation burden (TMB), often manifesting as neoepitope expression on the tumor cell surface recognized by effector immune cells. As a result, impaired DNA repair due to CHEK2 loss of function, either from germline deleterious variants or acquired mutations, results in the recruitment of CD8+ cytotoxic T-cells and subsequent efficacy of ICI treatment. However, functional loss of CHEK2 may be directly involved in potentiating the immune response through canonical inflammatory and anti-tumor pathways, acting through the cGAS-STING pathway. Although the exact mechanism by which CHEK2 modulates immune responses is still under investigation, combination therapy with CHEK1/2 inhibition and ICI immunotherapy has shown benefit in preclinical studies of several solid tumors.

Immunotherapy has recently cast great attention on cancer vaccines in order to aim to decrease tumor growth, elicit persistent anti-tumor memory, and avert adverse reactions. Moreover, cancer vaccines employ tumor antigens to stimulate anti-tumor immunity using different platforms, for example, whole cells, nucleic acids, peptides, etc. Recent findings have classified cancer vaccines into cell-based, virus-based, peptide-based, and nucleic acid-based types. Personalized cancer vaccines, also known as neoantigens, have exhibited acceptable safety and efficacy in eliciting immune responses against melanoma and glioblastoma. Neoantigen-based vaccines, concentrating on tumor antigens present only in cancer cells, bring intriguing opportunities for different types of cancer, including melanoma, lung, bladder, breast, renal, head and neck, and colorectal cancers. Furthermore, breast cancer research underscores ongoing trials of vaccines targeting α-lactalbumin to prevent the recurrence of triple-negative breast cancer. Lung cancer studies have discovered interesting outcomes with liposomal vaccines and the potential of CIMAvax-EGF in the prevention of lung cancer. Studies on ovarian cancer highlight personalized cancer vaccines using dendritic cells and various tumor-associated antigens to elicit T-cell responses against cancer cells. Overall, such advancements suggest great promise for future clinical translation of cancer novel immunotherapy-based approaches to effectively counter various types of cancer.

Cancer immunotherapy stimulates and enhances antitumor immune responses to eliminate cancer cells. Neoantigens, which originate from specific mutations within tumor cells, are key targets in cancer immunotherapy. Neoantigens manifest as abnormal peptide fragments or protein segments that are uniquely expressed in tumor cells, making them highly immunogenic. As a result, they activate the immune system, particularly T cell‑mediated immune responses, effectively identifying and eliminating tumor cells. Certain tumor‑associated antigens that are abnormally expressed in normal host proteins in cancer cells are promising targets for immunotherapy. Neoantigens derived from mutated proteins in cancer cells offer true cancer specificity and are often highly immunogenic. Furthermore, most neoantigens are unique to each patient, highlighting the need for personalized treatment strategies. The precise identification and screening of neoantigens are key for improving treatment efficacy and developing individualized therapeutic plans. The neoantigen prediction process involves somatic mutation identification, human leukocyte antigen (HLA) typing, peptide processing and peptide‑HLA binding prediction. The present review summarizes the major current methods used for neoantigen screening, available computational tools and the advantages and limitations of various techniques. Additionally, the present review aimed to summarize experimental strategies for validating the immunogenicity of the predicted neoantigens, which will determine whether these neoantigens can effectively trigger immune responses, as well as challenges encountered during neoantigen screening, providing relevant recommendations for the optimization of neoantigen‑based immunotherapy.

This white paper examines the potential of pioneering technologies and artificial intelligence-driven solutions in advancing clinical trials involving radiation therapy. As the field of radiation therapy evolves, the integration of cutting-edge approaches such as radiopharmaceutical dosimetry, FLASH radiation therapy, image guided radiation therapy, and artificial intelligence promises to improve treatment planning, patient care, and outcomes. Additionally, recent advancements in quantum science, linear energy transfer/relative biological effect, and the combination of radiation therapy and immunotherapy create new avenues for innovation in clinical trials. The paper aims to provide an overview of these emerging technologies and discuss their challenges and opportunities in shaping the future of radiation oncology clinical trials. By synthesizing knowledge from experts across various disciplines, this white paper aims to present a foundation for the successful integration of these innovations into radiation therapy research and practice, ultimately enhancing patient outcomes and revolutionizing cancer care.

T cell receptor (TCR)-engineered T cell therapy holds great promise for treating solid tumors, but the overall clinical efficacy remains limited. The vital challenge lies in the loss of TCR-targeted antigens and poor T cell persistence. Here, we demonstrate a novel approach to enhance TCR-T cell therapy and reject antigen-heterogeneous tumors through a multi-engineered T cell vaccine (Multi-Tvac). Multi-Tvac is composed of a TCR-targeted cognate peptide, tumor neoantigens, and an LAG-3Ig adjuvant signal, which significantly boosts dendritic cell (DC) maturation, enhances TCR-T cell anti-tumor function, and alleviates exhaustion phenotype. When combined with TCR-T cell therapy, Multi-Tvac induced long-lasting responses in established solid tumors resistant to TCR-T cell monotherapy. Notably, Multi-Tvac prevented antigen-loss tumor escape and achieved complete responses in an antigen-heterogeneous solid tumor model. Mechanistically, Multi-Tvac enhanced antigen presentation in secondary lymphoid organs (SLOs), orchestrating a strong endogenous immune response that primes T cells. As a proof-of-concept, our study extended T cell engineering beyond TCR-directed killing, which could perform as a therapeutic vaccination platform to empower TCR-T cells with new capabilities and overcome major barriers in the clinical treatment of solid tumors.

The spatial proteomic profiling of complex tissues is essential for investigating cellular function in physiological and pathological states. However, the imbalance among resolution, protein coverage, and expense precludes their systematic application to analyze whole tissue sections in an unbiased manner and with high resolution. Here, we introduce panoramic spatial enhanced resolution proteomics (PSERP), a method that combines tissue expansion, automated sample segmentation, and tryptic digestion with high-throughput proteomic profiling. The PSERP approach facilitates rapid quantitative profiling of proteomic spatial variability in whole tissue sections at sub-millimeter resolution. We demonstrated the utility of this method for determining the streamlined large-scale spatial proteomic features of gliomas. Specifically, we profiled spatial proteomic features for nine glioma samples across three different mutation types (IDH1-WT/EGFR-mutant, IDH1-mutant, and IDH1/EGFR-double-WT gliomas) at sub-millimeter resolution (corresponding to a total of 2,230 voxels). The results revealed over 10,000 proteins identified in a single slide, which helps us to portray the diverse proteins and pathways with spatial abundance patterns in the context of tumor heterogeneity and cellular features. Our spatial proteomic data revealed distinctive proteomic features of malignant and non-malignant tumor regions and depicted the distribution of proteins from tumor centers to tumor borders and non-malignant tumor regions. Through integrative analysis with single-cell transcriptomic data, we elucidated the cellular composition and cell-cell communications in a spatial context. Our PSERP also includes a spatially resolved tumor-specific peptidome identification workflow that not only enables us to elucidate the spatial expression patterns of tumor-specific peptides in glioma samples with different genomic types but also provides us with opportunities to select combinations of tumor-specific mutational peptides whose expression could cover the maximum tumor regions for future immune therapies. We further demonstrated that combining tumor-specific peptides might enhance the efficacy of immunotherapy in both patient-derived cell (PDC) and patient-derived xenograft (PDX) models. PSERP efficiently retains precise spatial proteomic information within the tissue context and provides a deeper understanding of tissue biology and pathology at the molecular level.

Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. Conventional interventions including surgery, radiotherapy, and chemotherapy provide only modest survival benefits, underscoring an urgent need for more effective therapies. Although immunotherapy has revolutionized the management of several solid tumors, its clinical benefit in pancreatic cancer has so far been disappointing. Mounting evidence indicates that a highly immunosuppressive tumor microenvironment (TME), dominated by tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), drives immune evasion, tumor progression, metastasis, and chemoresistance through complex cytokine and chemokine networks. This review summarizes current knowledge of these immunosuppressive mechanisms and provides emerging strategies aimed at re-educating or depleting these cellular constituents to enhance the efficacy of immunotherapy in pancreatic cancer.

T cells play a pivotal role in cancer immunotherapy by recognizing tumor-specific neoantigens presented on HLA molecules, which are specifically expressed on cancer cells. While neoantigens are generally unique to individual cancers, certain neoantigens, known as 'shared neoantigens' that are common in a subset of cancer patients, represent promising immunotherapeutic targets. We previously identified an immunogenic shared frameshift neoantigen, 1472SP2, derived from recurrent frameshift indel mutation cluster (APC-F2-1472*) in the APC gene and presented on HLA-A24:02. In this study, we attempted to identify an antibody targeting a complex formed by the APC 1472SP2 neoantigen and HLA-A24. Using the phage display library screening, we isolated single-chain variable fragments (scFvs) that specifically recognize the 1472SP2/HLA-A24 complex. We then designed a bispecific antibody (BsAb) that would connect T cells via an anti-CD3 scFv to the cancer-specific 1472SP2 presented on the HLA-A24 molecule. ELISA analysis revealed that BsAb specifically recognized both 1472SP2-HLA-A24 monomer and CD3 protein. When T cells were co-cultured with antigen-presenting cells expressing HLA-A24:02, IFN-γ release and cytotoxicity were observed only in the presence of 1472SP2-BsAb, indicating that the 1472SP2-BsAb effectively activated T cells to lyse target cells presenting this neoantigen. This approach implies an off-the-shelf, cancer selective approach to target cancers expressing shared neoantigens for patients who are difficult to treat with conventional therapies.

Gastric cancer (GC) is one of the primary contributors to cancer-related mortality on a global scale. It holds a position within the top five most prevalent malignancies both in terms of occurrence and fatality rates. Immunotherapy, as a breakthrough cancer treatment, brings new hope for GC patients. Various biomarkers, such as the expression of programmed death ligand-1 (PD-L1), the microsatellite instability (MSI) status, tumor mutational burden (TMB), and Epstein-Barr virus (EBV) infection, demonstrate potential to predict the effectiveness of immunotherapy in treating GC. Nevertheless, each biomarker has its own limitations, which leads to a significant portion of patients continue to be unresponsive to immunotherapy. With the understanding of the tumor immune microenvironment (TIME), genome sequencing technology, and recent advances in molecular biology, new molecular markers, such as POLE/POLD1mutations, circulating tumor DNA, intestinal flora, lymphocyte activation gene 3 (LAG-3), and lipid metabolism have emerged. This review aims to consolidate clinical evidence to offer a thorough comprehension of the existing and emerging biomarkers. We discuss the mechanisms, prospects of application, and limitations of each biomarker. We anticipate that this review will open avenues for fresh perspectives in the investigation of GC immunotherapy biomarkers and promote the precise choice of treatment modalities for gastric cancer patients, thereby advancing precision immuno-oncology endeavors.

Extracellular vesicles (EVs) have emerged as a cell-free therapeutic approach, garnering increasing attention for their potential to enhance the safety and efficacy of immunotherapy. This interest is primarily driven by the biocompatibility and cell/tissue tropism inherent to EVs, but also due to their reconfigurable content. This, termed as cargo, may comprise bioactive molecules as proteins, lipids, and nucleic acids that play a pivotal role in mediating intercellular communication. In particular, dendritic cells-derived extracellular vesicles (DC-EVs) facilitate the transfer of critical components, like antigens and immune-regulatory factors, and due to the expression of major histocompatibility complexes and co-stimulatory molecules on their surface can activate T cells, thereby modulating the immune response. Additionally, DC-EVs can be engineered to transport tumor-specific antigens, cytokines, or other agents in order to strength their immunotherapeutic potential, and even be used in vaccines formulation. In this review, the latest advancements in engineering DC-EVs to improve their immunotherapeutic potential is discussed in detail, while also addressing current challenges associated with DC-EVs therapies.

Features of constrained adaptive immunity and high neoantigen burden have been correlated with response to immune checkpoint inhibitors (ICIs). In an attempt to stimulate antitumor immunity, we evaluated atezolizumab (anti-programmed cell death protein 1 ligand 1) in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer. The primary endpoints were feasibility (as defined by neoantigen identification, peptide synthesis, vaccine production time and vaccine administration) and safety. Secondary endpoints included objective response rate, duration of response and progression-free survival for participants treated in the metastatic setting, time to progression for participants treated in the adjuvant setting, overall survival and vaccine-induced neoantigen-specific T cell immunity. A vaccine was successfully prepared (median 20.3 weeks) for 10 of 12 enrolled participants. All participants initiating treatment completed the priming cycle. The most common treatment-related adverse events were grade 1 injection site reactions, fatigue and fever. At a median follow-up of 39 months, three of four participants treated in the adjuvant setting were free of recurrence and two of five participants treated in the metastatic setting with measurable disease achieved an objective response. All participants demonstrated on-treatment emergence of neoantigen-specific T cell responses. Neoantigen vaccination plus ICI was feasible and safe, meeting its endpoints, and warrants further investigation. ClinicalTrials.gov registration: NCT03359239 .

Cancer originates from dysregulated cell proliferation driven by driver gene mutations. Despite numerous algorithms developed to identify genomic mutational signatures, they often suffer from high computational complexity and limited clinical applicability.

Here, we presented ProgModule, an advanced computational framework designed to identify mutation driver modules for cancer prognosis and immunotherapy response prediction. In ProgModule, we introduced the Prognosis-Related Mutually Exclusive Mutation (PRMEM) score, which optimizes the balance between exclusive mutation coverage and the incorporation of mutation combination mechanisms critical for cancer prognosis.

Applying to BLCA and HNSC cohorts, ProgModule successfully identified driver modules that stratify patients into distinct prognostic subgroups, and the combination of these modules could serve as an effective prognostic biomarker. Extending our method to diverse cancers, ProgModule presented robust prognostic performance and stability across model parameters, including stopping criteria and network topology. Moreover, our analysis suggested that driver modules can predict immunotherapeutic benefit more effectively than existing signatures. Further analyses based on published CRISPR data indicated that genes within these modules may serve as potential therapeutic targets.

Altogether, ProgModule emerges as a powerful tool for identifying mutation driver modules as prognostic and immunotherapy response biomarkers, and genes within these modules may be used as potential therapeutic targets for cancer, offering new insights into precision oncology.

Biliary tract cancers (BTCs) are a heterogeneous group of tumors arising from cells in the bile ducts and gallbladder. The 5-year overall survival rate for all BTC stages combined is ~20%, and treatment options for patients with unresectable disease are limited, leaving an unmet clinical need. In recent years, significant efforts have been made to refine and implement targeted therapeutic approaches for patients with BTC. The adoption of early and comprehensive molecular profiling is crucial to identifying patients who may be candidates for effective targeted therapies. Characterization of the molecular landscape of BTCs led to the identification of murine double minute 2 homolog gene (MDM2) amplification across all BTC subtypes. The MDM2 protein is a critical negative regulator of p53 stabilization and activity that is an emerging actionable biomarker in BTCs. There are multiple therapeutic approaches that aim to target MDM2 activity, thereby restoring the intrinsic tumor suppressor function of p53 and halting oncogenesis. However, these have been limited by our evolving understanding of the role of MDM2 in BTC pathogenesis. Here, we offer a review of the current understanding of the role of MDM2 in BTC biology and its therapeutic implications.

Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for response to immune checkpoint inhibitors. We report updated results including objective response rate, progression free survival, and overall survival data with 5-year follow-up in recurrent platinum-resistant, MSI-H, endometrial cancer (EC) patients fully sequenced using whole exome sequencing (WES) and treated within a prospective phase II study with pembrolizumab (NCT02899793).

Tumors from patients with measurable MSI-H/dMMR endometrial cancer confirmed by immunohistochemistry, polymerase chain reaction, and MLH-1 methylation assays were sequenced using whole exome sequencing and the FoundationOne platform for the identification of Lynch, Lynch-like, and MLH-1 methylated characteristics before receiving pembrolizumab 200 mg every 3 weeks for up to 24 months. The primary endpoint was objective response rate (ORR), and secondary endpoints were progression free survival (PFS), and overall survival (OS).

After almost 97 person-years of follow-up, the Lynch-like subgroup (n = 6) of MSI-H/dMMR patients continues to exhibit better ORR than the methylated (n = 18) subgroup (100 % versus 44 %, Fisher's exact P = 0.024), as well as improved PFS (unreached for Lynch-like versus 14.6 months, Log-Rank P = 0.005) and improved OS (unreached for Lynch-like versus 32.6 months, Log-Rank P = 0.058). Toxicity was manageable in both groups of MSI-H patients.

Mature follow-up results continue to suggest the prognostic significance of Lynch-like versus methylated MSI-H/dMMR features in endometrial cancer patients treated with pembrolizumab in terms of ORR, PFS, and OS. Stratification for these translational aspects may be warranted in future clinical trials with immune checkpoint inhibitors in MSI-H/dMMR endometrial cancer patients.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited targeted therapies and high recurrence rates. While immune checkpoint inhibitors (ICIs) have shown promise, their efficacy as monotherapy is limited. Clinically, ICIs demonstrate significant benefit primarily when combined with chemotherapy, particularly in the neoadjuvant setting for early-stage TNBC, which yields superior outcomes compared to adjuvant therapy. This review elucidates the tumor immunological principles underlying these observations. We discussed how the suppressive tumor microenvironment (TME), progressive T cell exhaustion, and associated epigenetic scarring constrain ICI monotherapy effectiveness. Crucially, we highlight the immunological advantages of the neoadjuvant approach: the presence of the primary tumor provides abundant antigens, and intact tumor-draining lymph nodes (TDLNs) act as critical sites for ICI-mediated priming and expansion of naïve and precursor exhausted T cells. This robust activation within TDLNs enhances systemic anti-tumor immunity and expands the T cell repertoire, a process less effectively achieved in the adjuvant setting after tumor resection. These mechanisms provide a strong rationale for the improved pathological complete response (pCR) rates and event-free survival observed with neoadjuvant chemoimmunotherapy, as demonstrated in trials like KEYNOTE-522. We further explore the implications for adjuvant therapy decisions based on treatment response, the challenges of ICI resistance, the need for predictive biomarkers, management of immune-related adverse events (irAEs), and future therapeutic directions. Understanding the dynamic interplay between chemotherapy, ICIs, T cells, and the TME, particularly the role of TDLNs in the neoadjuvant context, is essential for optimizing immunotherapy strategies and improving outcomes for patients with TNBC.

The PGV001 platform is feasible, safe, and immunogenic. The OpenVax pipeline predicted immunogenic neoantigens in tumors with wide-ranging mutational burdens. Data from this study prompted three additional PGV001 trials, one in newly diagnosed glioblastoma, one in urothelial cancer in combination with an ICI, and another in prostate cancer.

Tumor neoantigens, defined as tumor-specific antigens arising from somatic mutations, have shown great potential as targets for cancer vaccines in clinical studies. However, the number of neoantigens capable of effectively activating immune responses is quite limited. Over the past few decades, tumor neoantigen vaccines based on MHC-I epitopes that activate CD8+ T cells have been extensively studied. However, growing evidence suggests that CD4+ T cells are important in cancer immunotherapy. In contrast to CD8+ T cells, the receptors on CD4+ T cells exhibit a wider range of antigen peptide-MHC recognition, which can detect more tumor mutation antigens. In our earlier studies, a nitrated CD4+ T-cell epitope (NitraTh) was constructed as a novel CD4+ T-cell epitope that can enhance the immunogenicity of multiple tumor antigens. Therefore, we designed vaccines targeting MHC-II neoantigen epitopes using the nitrated T-cell epitope containing immunogenic amino acids. We found that vaccines conjugated with NitraTh exhibited enhanced immunogenicity. Crucially, the NitraTh-modified MHC-II tumor neoantigen vaccines increased the proportion of CD4+ T cells that infiltrate tumors and the spleen, elevated the expression of several cytokines with antitumor effects and facilitated the transformation of CD4+ T cells into Th1 cells, thereby reducing tumor growth. Additionally, the nitrated epitope has been shown to transform naïve CD4+ T cells into effector memory cells, thus facilitating enduring antitumor actions. The strategy of combining nitrated epitopes with MHC-II neoantigen epitopes confirms the significance of CD4+ T-cell immunity in cancer and may provide a novel approach for cancer vaccine design. SIGNIFICANCE STATEMENT: This study presents a novel design paradigm for tumor vaccines-combining MHC-II epitopes with nitrated CD4+ T-cell epitopes. This approach promotes the differentiation of CD4+ T cells toward a Th1 phenotype and generates long-lasting effector memory CD4+ T cells. Under the enhanced effects of CD4+ T cells, the vaccines we designed achieved superior antitumor efficacy and improved the immunosuppressive tumor microenvironment.

Effective immune responses in both the spleen and the tumor microenvironment are crucial for cancer immunotherapy. However, delivery of neoantigen peptide vaccines to antigen-presenting cells (APCs) at these sites remains challenging. In this study, LNPsD18, a cationic liposomal formulation that targets and enhances APC uptake at both sites without modifying the targeting ligands is developed. By co-delivering tumor-specific neoantigens and a cholesterol-coupled toll-like receptor 9 (TLR9) agonist within LNP-vaxD18, an approximately 60-fold increase in dendritic cell uptake compared to neoantigen-adjuvant mixtures is achieved. Intravenous administration of the liposome-neoantigen peptide vaccine targets both the spleen and the tumor, boosting splenic DC activation, increasing M1-type tumor-associated macrophages, and elevating tumor cytokine levels. This reshapes the tumor microenvironment, enhancing IFN-γ-producing CD8+ T cells and TCF1+CD8+ T cells within tumors. These outcomes significantly inhibit established tumor growth compared to nontargeted lipid-based nanovaccine formulations, resulting in improved survival in orthotopic hepatocellular carcinoma and colorectal cancer models. The findings highlight the importance of targeting APCs in both the spleen and tumors to optimize the therapeutic efficacy of liposome-neoantigen vaccines in cancer treatment.

Tertiary lymphoid structure (TLS) has been reported to be associated with prognosis and immunotherapy in certain cancers. The objective of our study was to investigate the prognostic significance of Tertiary Lymphoid Structures (TLS) within the context of Muscle-Invasive Bladder Cancer (MIBC), while concurrently examining the clinicopathological and molecular determinants influencing TLS formation.

Immunohistochemistry was used to detect the expression of TLS, CD8+ T cells, B cells, and plasma cells in 119 MIBC cases, of which 80 cases were tested by next generation sequencing (NGS) for analyzing the differences in gene alterations between TLS-negative and TLS-positive.

TLS were identified in 52.1% (62/119) of the MIBC cases studied. Patients exhibiting TLS demonstrated reduced T and TNM staging and prolonged overall survival (OS) compared to those lacking TLS. Multivariate analysis showed that TLS was an independent prognostic factor. Densities of B cells, CD8+ T cells, and plasma cells in tumors were significantly correlated with TLS, but in the cases with low-density B cells, high-density CD8+ T cells, or high-density plasma cells, differences in OS between the tumors with TLS and without TLS were not significant. Compared with TLS-negative tumors, TLS-positive tumors had a lower frequency of TP53 mutations and higher frequencies of FAT1 and CDKN1A mutations. Tumor mutational burden (TMB) was not significantly different between the two groups but was significantly associated with TLS in TP53 wild-type tumors.

TLS emerged as an independent harbinger of favorable prognosis in MIBC, predominantly mediating antitumor responses via B cells. Moreover, TP53 mutations were identified as a potential inhibitor of TLS formation.

Lung cancer is one of the most common malignant tumors, of which non-small cell lung cancer (NSCLC) accounts for about 85 %. Although immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, have significantly improved the prognosis of patients with NSCLC. There are still many patients do not benefit from ICIs. Primary resistance remains a major challenge in advanced NSCLC. The cancer-immunity cycle describes the process from antigen release to T cell recognition and killing of the tumor, which provides a framework for understanding anti-tumor immunity. The classical cycle consists of seven steps, and alterations at each stage can result in resistance. This review examines the current status of PD-1/PD-L1 blockade in the treatment of advanced NSCLC and explores potential mechanisms of resistance. We summarize the latest clinical trials of PD-1/PD-L1 inhibitors combined with other therapies and explore potential targets for overcoming primary resistance to PD-1/PD-L1 inhibitors.

The stimulator of interferon genes (STING) pathway has emerged as a new immunotherapy strategy with potent local stimulation specificity, showing promising potential to counteract the immunosuppression in glioma. Herein, a tumor microenvironment (TME) responsive nanoagonists are developed based on an organic-inorganic copolymer composed of the polymer PC6AB coupled with manganous phosphate ionic oligomers (MnP). The degradation of nanoagonists into PC6AB and MnP in the acidic TME enables spatiotemporal control of their delivery to tumor cells and immune cells, respectively. PC6AB with membranolytic activity selectively interacts with tumor cell membranes to induce immunogenic cell death, while manganese metal can activate the STING pathway in immune cells and trigger downstream immunostimulatory signals. Nanoagonists can stimulate robust antitumor immunity after local injection into the brain extracellular space (ECS), showing significant therapeutic efficacy in mouse glioma. Nanoagonists can achieve spatiotemporal orchestration of STING activation in response to TME and enhance immune response against "cold" solid tumors, providing a promising approach for clinical immunotherapy.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide, and early pathological diagnosis is crucial for formulating treatment plans. Despite the widespread attention to pathology in the treatment of HCC patients, a large amount of information contained in pathological images is often overlooked.

We retrospectively collected clinical data and pathological slide images from (a) 331 HCC patients at Qingdao University Affiliated Hospital between January 2013 and December 2016 and (b) 180 HCC patients from The Cancer Genome Atlas (TCGA). After data screening, precise quantification of various cell types was achieved using QuPath software. Key factors related to the survival prognosis of pathologically confirmed HCC patients were identified through Cox regression and neural network models, and potential therapeutic targets were screened.

Our study showed that tumour-infiltrating lymphocytes (TILs) had a protective effect. We quantified the TILs index by machine learning and built a neural network model to predict the prognostic risk of patients (ROC = 0.836 for training set ROC validation set). 95% CI [0.7688-0.896], and there was a significant difference in prognosis in the high-low risk group predicted by the model (p = 2.6e-18, HR = 0.18, 95% CI [0.12-0.27], and TNFSF4 was identified as a possible immunotherapy target.

This study included a total of 511 patients, divided into a training cohort of 331 cases (from Qingdao University Hospital between January 2013 and December 2016) and a validation cohort of 180 cases (TCGA). The results revealed that tumor-infiltrating lymphocytes (TILs) have a protective effect and successfully predicted the survival risk of liver cancer patients using machine learning and neural network technology. The discovery of TNFSF4 provides a new potential target for immunotherapy.

Next-generation sequencing (NGS) has emerged as a pivotal technology in the field of oncology, transforming the approach to cancer diagnosis and treatment. This paper provides a comprehensive overview of the integration of NGS into clinical settings, emphasizing its significant contributions to precision medicine. NGS enables detailed genomic profiling of tumors, identifying genetic alterations that drive cancer progression and facilitating personalized treatment plans targeting specific mutations, thereby improving patient outcomes. This capability facilitates the development of personalized treatment plans targeting specific mutations, leading to improved patient outcomes and the potential for better prognosis. The application of NGS extends beyond identifying actionable mutations; it is instrumental in detecting hereditary cancer syndromes, thus aiding in early diagnosis and preventive strategies. Furthermore, NGS plays a crucial role in monitoring minimal residual disease, offering a sensitive method to detect cancer recurrence at an early stage. Its use in guiding immunotherapy by identifying biomarkers that predict response to treatment is also highlighted. Ethical issues related to genetic testing, such as concerns around patient consent and data privacy, are also important considerations that need to be addressed for the broader implementation of NGS. These include the complexities of data interpretation, the need for robust bioinformatics support, cost considerations, and ethical issues related to genetic testing. Addressing these challenges is essential for the widespread adoption of NGS. Looking forward, advancements such as single-cell sequencing and liquid biopsies promise to further enhance the precision of cancer diagnostics and treatment. This review emphasizes the transformative impact of NGS in oncology and advocates for its incorporation into routine clinical practice to promote molecularly driven cancer care.

Recent studies suggest that CD4+ T cells can exert potent anti-tumor effects and improve immunotherapy efficacy by aiding CD8+ T cells. However, characterizing the mechanism of CD4+ T cells' anti-tumor activity has been challenging due to inaccurate major histocompatibility complex class II (MHC-II) peptide prediction algorithms and the lack of high-quality reagents for immune monitoring. To address this, we developed MHC2-substitution of CLIP and analytical LCMS evaluation (MHC2-SCALE), a streamlined approach combining affinity optimized class II-associated invariant chain peptide (CLIP) exchange technology, high throughput 2D-LCMS analysis, and rapid generation of peptide-bound MHC-II monomers for subsequent multimer assembly. We validated MHC-II peptide candidates predicted by the immune epitope database (IEDB) algorithm, as well as uncovered many true and immunogenic MHC-II binders that were not predicted by IEDB. Thus, MHC2-SCALE expands the opportunities for discovering, tracking, and phenotyping antigen-specific CD4+ T cells in preclinical and clinical settings, thereby improving therapies for cancer, autoimmunity, or infectious diseases.

Cancer immunotherapy is a beneficial therapy for many cancer types, but predictive pan-tumor biomarkers for clinical benefit are suboptimal. Our study, employing DNA and RNA based analysis, investigated the role of predicted neoantigens in the benefits of immunotherapy within a cohort of 88 patients of European descent with advanced solid tumors. Patients who had a prolonged (> 12 months) duration of immunotherapy exhibited heightened immune responses, characterized by increased levels of predicted neoantigens with strong HLA binding potential, elevated cytotoxic marker levels, and enhanced T cell activity. Furthermore, our analysis revealed associations between prolonged duration of therapy and rare variants, notably within the EPHA8 gene. These variants, exclusive to patients with a prolonged (> 12 months) duration of immunotherapy, suggest potential implications for immunotherapy response. In addition, the evolutionary conservation of these variants across vertebrate species underscores their functional importance in tumor biology and ultimately, treatment outcomes. Despite limitations in sample size and patient homogeneity, our findings emphasize the potential utility of understanding the molecular and immunological mechanisms underlying immunotherapy responses to further refine personalized treatment strategies.

Radiotherapy is a standard cancer treatment that involves the induction of DNA damage. DNA damage repair (DDR) pathways maintain genomic integrity and make tumors resistant to radiotherapy and certain chemotherapies. In turn, DDR dysfunction results in cumulative DNA damage, leading to increased sensitivity for antitumor treatment. Moreover, radiotherapy has been shown to trigger antitumor immunity. Currently, immunotherapy has become a new and widely used standard strategy for treating a broad spectrum of tumor types. Notably, recent studies have demonstrated that DDR pathways play important roles in driving the response to immunotherapy. Herein, we review and discuss how DDR affects antitumor immunity induced by radiotherapy. Furthermore, we summarize the development of strategies for combining DDR inhibitors with radiotherapy and/or immunotherapy to enhance their efficacy against cancers.

While immune checkpoint therapy (ICT) has revolutionized cancer treatment, most patients with advanced disease fail to achieve durable benefit. To address this challenge, it is essential to integrate mechanistic research with clinical studies to: (1) understand response mechanisms, (2) identify patient-specific resistance pathways, (3) develop biomarkers for patient selection, and (4) design novel therapies to overcome resistance. We propose that incorporating "direct-in-patient" studies into clinical trials is crucial for bridging the gap between fundamental science and clinical oncology. In this review, we first highlight recent clinical success of ICT in the neoadjuvant setting, where treatment is given in earlier disease stages to improve outcomes. We then explore how neoadjuvant clinical trials could be utilized to drive mechanistic laboratory-based investigations. Finally, we discuss novel scientific concepts that will potentially aid in overcoming resistance to ICT, which will require future clinical trials to understand their impact on human immune responses.

The tumor-immune response is mobilized to suppress tumorigenesis, while the immune microenvironment and lymph node microenvironment are formed gradually during tumor progression. In fact, tumor surface antigens are not easily recognized by antigen-presenting cells. So it is hard for the immune system to kill the newly formed tumor cells effectively. In a normal immune environment, immune function is always suppressed to maintain the stability of the body, and regulatory T cells play an important role in maintaining immune suppression. However, during tumorigenesis, the suppression of regulatory T cell immune functions is more likely to contribute to tumor cell proliferation and migration leading directly to tumor progression. Therefore, focusing on the role of regulatory T cells in tumor immunity could improve tumor immunotherapy outcomes in the clinic. Regulatory T cells are more mature in hematologic system tumors than in solid tumors. However, there are continuing efforts to apply regulatory T cells for immunotherapy in solid tumors. This review describes the role of regulatory T cells in solid tumor immunotherapy from the perspective of prognosis, immune microenvironment remodeling, and current clinical applications. This summary could help us better understand the mechanisms of regulatory T cells in solid tumor immunotherapy and further expand their clinical application.

Three hallmarks of ICD (immunogenic cell death), release of adenosine triphosphate (ATP), release of high mobility group box 1 protein, and calreticulin exposure on the cell surface, were studied upon treatment of mammalian cells with small cyclic peptides, namely, the natural antibiotic gramicidin S (GS) and two photocontrolled GS analogues (LMB002 and LMB033). The analogues contained a photoisomerizable diarylethene fragment, and they exhibited different bioactivities in their "open" and "closed" photoisomeric forms. The data (obtained from cell cultures and spheroids) were collected in a concentration-dependent manner to assess cytotoxicity. Results showed that treatment with all peptides induced ICD at sub-IC50 and higher concentrations, indicating that GS and its derivatives have promising immunogenic potential. The "open" photoisomers of the photoswitchable GS analogues generated using visible light were as efficient as ICD inducers and the parent GS, while the UV-generated "closed" photoforms induced ICD only at higher concentrations. Herein, the cell specificity and time dependency of the observed effects are presented.

CD44, a widely recognized cancer stem cell marker, displayed a vital participation in the cancer immune invasion and may related with the response to the immunotherapy. However, the role of CD44 in cancer immunology is not well defined. Therefore, we intended to explore its prognostic value and potential immunological functions across 33 human cancer types.

Based on the data of patients from The Cancer Genome Atlas (TCGA), Sangerbox was used to analyze the correlations between CD44 expression and tumor-infiltrated immune cells, immune checkpoints, neoantigens, microsatellite instability (MSI), and tumor mutational burden (TMB) in human cancers. A mouse model xenografted with shRNA-CD44 MC38 was established.

The elevated CD44 was associated with tumor stage and prognosis in several different cancers. GSEA results showed that upregulated CD44 involved in cancer stem cell associated process, antigen processing and presentation, and immune cells proliferation and activation. CD44 plays an essential role in the tumor immune regulation and immune checkpoints inhibitor response. The correlation of CD44 gene expression and infiltration levels of immune cells varied across different cancer types. Notably, the upregulation of CD44 expression is positively correlated with regulatory CD4 T cells, macrophages M1 and M2 in several analyzed cancers. Furthermore, we verified the effect of CD44 on tumor growth and immune microenvironment in mouse xenografted with shRNA-CD44 MC38. Moreover, DNA methylation existed in CD44 expression and associated with dysfunctional T-cell phenotypes via different mechanisms, thus resulting in tissue-dependent prognoses.

CD44 is both a cancer stem cell marker and a potential prognostic and immunological biomarker in various malignant tumors. Moreover, CD44 could be a novel target for immune-based therapy.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the United States, with poor overall survival across all stages. Less than 20% of patients are eligible for curative surgical resection at diagnosis, and despite adjuvant chemotherapy, most will experience disease recurrence within two years. The incorporation of immune-based strategies in the adjuvant setting remains an area of intense investigation with unrealized promise. It offers the potential of providing durable disease control for micro-metastatic disease following curative intent surgery and enabling personalized treatments based on mutational neoantigen profiles derived from resected specimens. However, most of these attempts have failed to demonstrate significant clinical success, likely due to the immunosuppressive tumor microenvironment (TME) and individual genetic heterogeneity. Despite these challenges, immune-based strategies, such as therapeutic vaccines targeted towards neoantigens, have demonstrated promise via immune activation and induction of T-cell tumor infiltration. In this review, we will highlight the foundational lessons learned from previous clinical trials of adjuvant immunotherapy, discussing the knowledge gained from analyses of trials with disappointing results. In addition, we will discuss how these data have been incorporated to design new agents and study concepts that are proving to be exciting in more recent trials, such as shared antigen vaccines and combination therapy with immune-checkpoint inhibitors and chemotherapy. This review will evaluate novel approaches in ongoing and future clinical studies and provide insight into how these immune-based strategies might evolve to address the unique challenges for treatment of PDAC in the adjuvant setting.

Polyamines have tantalized cancer researchers as a potential means to rein in the rampant growth of cancer cells. However, clinical trials in recent decades have disappointed in delivering notable progress. Herein, a microfluidic-assisted synthetic hydrogen-bond organic framework (HOF) as a polyamine-depleting nanoplatforms designed to unleash the vigor of both dendritic cells (DCs) and T cells for precision cancer immunotherapy is reported. Upon internalization by tumor cells, the loaded plasma amine oxidase (PAO) in HOF efficiently depletes polyamines, remolding the tumor microenvironment and alleviating T-cell immunosuppression. This process also generates acrolein and H2O2, triggering CRISPR-assisted neoantigen generation. Specifically, Acrolein induces carbonyl stress, increasing mutational burdens. Simultaneously, HOF leverages the energy from the bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO)-H2O2 reaction for CRET-triggered singlet oxygen production, leading to thioether bond cleavage and release CRISPR-Cas9. Once released, CRISPR-Cas9 knocks out the DNA mismatch repair (MMR)-related MLH1 gene, further elevating mutational burdens and generating neoantigens, ideal targets for DCs. This dual-action strategy not only corrects T-cell immunosuppression but also enhances DC efficacy, presenting a powerful approach for tumor immunotherapy.